Combination therapy with glutaminase inhibitors

ABSTRACT

The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.

BACKGROUND

Glutamine supports cell survival, growth and proliferation throughmetabolic and non-metabolic mechanisms. In actively proliferating cells,the metabolism of glutamine to lactate, also referred to as“glutaminolysis” is a major source of energy in the form of NADPH. Thefirst step in glutaminolysis is the deamination of glutamine to formglutamate and ammonia, which is catalyzed by the glutaminase enzyme(GLS). Thus, deamination via glutaminase is a control point forglutamine metabolism.

Ever since Warburg's observation that ascites tumor cells exhibited highrates of glucose consumption and lactate secretion in the presence ofoxygen (Warburg, 1956), researchers have been exploring how cancer cellsutilize metabolic pathways to be able to continue activelyproliferating. Several reports have demonstrated how glutaminemetabolism supports macromolecular synthesis necessary for cells toreplicate (Curthoys, 1995; DeBardinis, 2008).

Thus, glutaminase has been theorized to be a potential therapeutictarget for the treatment of diseases characterized by activelyproliferating cells, such as cancer. The lack of suitable glutaminaseinhibitors has made validation of this target impossible. Therefore, thecreation of glutaminase inhibitors that are specific and capable ofbeing formulated for in vivo use could lead to a new class oftherapeutics.

SUMMARY OF INVENTION

The present invention provides a method of treating or preventingcancer, such as triple-negative breast cancer (TNBC), in a subject,comprising administering a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

-   L represents CH₂SCH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂, CH₂S, SCH₂, CH₂NHCH₂,    CH═CH, or

preferably CH₂CH₂, wherein any hydrogen atom of a CH or CH₂ unit may bereplaced by alkyl or alkoxy, any hydrogen of an NH unit may be replacedby alkyl, and any hydrogen atom of a CH₂ unit of CH₂CH₂, CH₂CH₂CH₂ orCH₂ may be replaced by hydroxy;

-   X, independently for each occurrence, represents S, O or CH═CH,    preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be    replaced by alkyl;-   Y, independently for each occurrence, represents H or CH₂O(CO)R₇;-   R₇, independently for each occurrence, represents H or substituted    or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl,    heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy;-   Z represents H or R₃(CO);-   R₁ and R₂ each independently represent H, alkyl, alkoxy or hydroxy;-   R₃, independently for each occurrence, represents substituted or    unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy,    heteroaryloxyalkyl or C(R₈)(R₉)(R₁₀), N(R₄)(R₅) or OR₆, wherein any    free hydroxyl group may be acylated to form C(O)R₇;-   R₄ and R₅ each independently represent H or substituted or    unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇;-   R₆, independently for each occurrence, represents substituted or    unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇; and-   R₈, R₉ and R₁₀ each independently represent H or substituted or    unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino,    aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or    heteroaryloxyalkyl, or R₈ and R₉ together with the carbon to which    they are attached, form a carbocyclic or heterocyclic ring system,    wherein any free hydroxyl group may be acylated to form C(O)R₇, and    wherein at least two of R₈, R₉ and R₁₀ are not H; and-   a taxane, such as paclitaxel, protein-bound paclitaxel    (nab-paclitaxel), cabazitaxel or docetaxel;-   wherein the subject is refractory to at least one prior chemotherapy    treatment, preferably to treatment with a taxane.

In certain embodiments, the present invention provides a pharmaceuticalpreparation suitable for use in a human patient in the treatment orprevention of cancer, such as triple-negative breast cancer, comprisingan effective amount of any of the compounds described herein (e.g., acompound of the invention, such as a compound of formula I), and one ormore pharmaceutically acceptable excipients. In certain embodiments, thepharmaceutical preparations may be for use in treating or preventing acondition or disease as described herein. In certain embodiments, thepharmaceutical preparations have a low enough pyrogen activity to besuitable for intravenous use in a human patient.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the GLS activity in TNBC cell lines, which correlates withsensitivity to CB-839.

FIG. 2 shows that CB-839 enhances the anti-tumor activity of paclitaxelin an in vivo TNBC model.

FIG. 3 shows the time TNBC patients remained in a clinical study oftreatment with CB-839 and paclitaxel.

FIG. 4 shows the RECIST response for TNBC patients by dose in a clinicalstudy of treatment with CB-839 and paclitaxel.

FIG. 5 shows the RECIST response for TNBC patients over time in aclinical study of treatment with CB-839 and paclitaxel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating or preventingcancer, such as triple-negative breast cancer in a subject, comprisingadministering a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

-   L represents CH₂SCH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂, CH₂S, SCH₂, CH₂NHCH₂,    CH═CH, or

preferably CH₂CH₂, wherein any hydrogen atom of a CH or CH₂ unit may bereplaced by alkyl or alkoxy, any hydrogen of an NH unit may be replacedby alkyl, and any hydrogen atom of a CH₂ unit of CH₂CH₂, CH₂CH₂CH₂ orCH₂ may be replaced by hydroxy;

-   X, independently for each occurrence, represents S, O or CH═CH,    preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be    replaced by alkyl;-   Y, independently for each occurrence, represents H or CH₂O(CO)R₇;-   R₇, independently for each occurrence, represents H or substituted    or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl,    heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy;-   Z represents H or R₃(CO);-   R₁ and R₂ each independently represent H, alkyl, alkoxy or hydroxy;-   R₃, independently for each occurrence, represents substituted or    unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy,    heteroaryloxyalkyl or C(R₈)(R₉)(R₁₀), N(R₄)(R₅) or OR₆, wherein any    free hydroxyl group may be acylated to form C(O)R₇;-   R₄ and R₅ each independently represent H or substituted or    unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇;-   R₆, independently for each occurrence, represents substituted or    unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇; and-   R₈, R₉ and R₁₀ each independently represent H or substituted or    unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino,    aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or    heteroaryloxyalkyl, or R₈ and R₉ together with the carbon to which    they are attached, form a carbocyclic or heterocyclic ring system,    wherein any free hydroxyl group may be acylated to form C(O)R₇, and    wherein at least two of R₈, R₉ and R₁₀ are not H; and-   a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or    docetaxel;

wherein the subject is refractory to at least one prior chemotherapytreatment, preferably refractory to treatment with a taxane.

In certain embodiments wherein alkyl, hydroxyalkyl, amino, acylamino,aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl,arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,heteroaryloxy, or heteroaryloxyalkyl are substituted, they aresubstituted with one or more substituents selected from substituted orunsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl),alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy,aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g.,trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino,hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy,aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl(e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl,heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl,amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl,or acyl, including perfluoroacyl (e.g., C(O)CF₃)), carbonylalkyl (suchas carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl,including perfluoroacylalkyl (e.g., -alkylC(O)CF₃)), carbamate,carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone,sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl,alkylthio, thiocarbonyl (such as thioester, thioacetate, orthioformate), phosphoryl, phosphate, phosphonate or phosphinate.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂,CH₂S, SCH₂, or CH₂NHCH₂, wherein any hydrogen atom of a CH₂ unit may bereplaced by alkyl or alkoxy, and any hydrogen atom of a CH₂ unit ofCH₂CH₂, CH₂CH₂CH₂ or CH₂ may be replaced by hydroxyl. In certainembodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂. In certainembodiments, L represents CH₂CH₂. In certain embodiments, L is notCH₂SCH₂.

In certain embodiments, Y represents H.

In certain embodiments, X represents S or CH═CH. In certain embodiments,one or both X represents CH═CH. In certain embodiments, each Xrepresents S. In certain embodiments, one X represents S and the other Xrepresents CH═CH.

In certain embodiments, Z represents R₃(CO). In certain embodimentswherein Z is R₃(CO), each occurrence of R₃ is not identical (e.g., thecompound of formula I is not symmetrical).

In certain embodiments, R₁ and R₂ each represent H.

In certain embodiments, R₃ represents arylalkyl, heteroarylalkyl,cycloalkyl or heterocycloalkyl. In certain embodiments, R₃ representsC(R₈)(R₉)(R₁₀), wherein R₈ represents aryl, arylalkyl, heteroaryl orheteroaralkyl, such as aryl, arylalkyl or heteroaryl, R₉ represents H,and R₁₀ represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, such ashydroxy, hydroxyalkyl or alkoxy.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂, suchas CH₂CH₂, CH₂S or SCH₂, Y represents H, X represents S, Z representsR₃(CO), R₁ and R₂ each represent H, and each R₃ represents arylalkyl,heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain suchembodiments, each occurrence of R₃ is identical.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂, Yrepresents H, X represents S, Z represents R₃(CO), R₁ and R₂ eachrepresent H, and each R₃ represents C(R₈)(R₉)(R₁₀), wherein R₈represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl,arylalkyl or heteroaryl, R₉ represents H, and R₁₀ represents hydroxy,hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl oralkoxy. In certain such embodiments, each occurrence of R₃ is identical.

In certain embodiments, L represents CH₂CH₂, Y represents H, Xrepresents S or CH═CH, Z represents R₃(CO), R₁ and R₂ each represent H,and each R₃ represents substituted or unsubstituted arylalkyl,heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain suchembodiments, each X represents S. In other embodiments, one or bothoccurrences of X represents CH═CH, such as one occurrence of Xrepresents S and the other occurrence of X represents CH═CH. In certainembodiments of the foregoing, each occurrence of R₃ is identical. Inother embodiments of the foregoing wherein one occurrence of Xrepresents S and the other occurrence of X represents CH═CH, the twooccurrences of R₃ are not identical.

In certain embodiments, L represents CH₂CH₂, Y represents H, Xrepresents S, Z represents R₃(CO), R₁ and R₂ each represent H, and eachR₃ represents C(R₈)(R₉)(R₁₀), wherein R₈ represents aryl, arylalkyl orheteroaryl, R₉ represents H, and R₁₀ represents hydroxy, hydroxyalkyl oralkoxy. In certain such embodiments, R₈ represents aryl and R₁₀represents hydroxyalkyl. In certain such embodiments, each occurrence ofR₃ is identical.

In certain embodiments wherein L represents CH₂, CH₂CH₂CH₂ or CH₂CH₂, Xrepresents O, and Z represents R₃(CO), both R₃ groups are not alkyl,such as methyl, or C(R₈)(R₉)(R₁₀), wherein R₈, R₉ and R₁₀ are eachindependently hydrogen or alkyl.

In certain embodiments wherein L represents CH₂CH₂, X represents S, andZ represents R₃(CO), both R₃ groups are not phenyl or heteroaryl, suchas 2-furyl.

In certain embodiments wherein L represents CH₂CH₂, X represents O, andZ represents R₃(CO), both R₃ groups are not N(R₄)(R₅) wherein R₄ isaryl, such as phenyl, and R₅ is H.

In certain embodiments wherein L represents CH₂SCH₂, X represents S, andZ represents R₃(CO), both R₃ groups are not aryl, such as optionallysubstituted phenyl, aralkyl, such as benzyl, heteroaryl, such as2-furyl, 2-thienyl or 1,2,4-trizole, substituted or unsubstituted alkyl,such as methyl, chloromethyl, dichloromethyl, n-propyl, n-butyl, t-butylor hexyl, heterocyclyl, such as pyrimidine-2,4(1H,3H)-dione, or alkoxy,such as methoxy, pentyloxy or ethoxy.

In certain embodiments wherein L represents CH₂SCH₂, X represents S, andZ represents R₃(CO), both R₃ groups are not N(R₄)(R₅) wherein R₄ isaryl, such as substituted or unsubstituted phenyl (e.g., phenyl,3-tolyl, 4-tolyl, 4-bromophenyl or 4-nitrophenyl), and R₅ is H.

In certain embodiments wherein L represents CH₂CH₂CH₂, X represents S,and Z represents R₃(CO), both R₃ groups are not alkyl, such as methyl,ethyl, or propyl, cycloalkyl, such as cyclohexyl, or C(R₈)(R₉)(R₁₀),wherein any of R₈, R₉ and R₁₀ together with the C to which they areattached, form any of the foregoing.

In certain embodiments, the compound is not one of the following:

The present invention further provides a method of treating orpreventing cancer, such as triple-negative breast cancer, in a subject,comprising administering a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein:

-   L represents CH₂SCH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂, CH₂S, SCH₂, CH₂NHCH₂,    CH═CH, or

preferably CH₂CH₂, wherein any hydrogen atom of a CH or CH₂ unit may bereplaced by alkyl or alkoxy, any hydrogen of an NH unit may be replacedby alkyl, and any hydrogen atom of a CH₂ unit of CH₂CH₂, CH₂CH₂CH₂ orCH₂ may be replaced by hydroxy;

-   X represents S, O or CH═CH, preferably S or CH═CH, wherein any    hydrogen atom of a CH unit may be replaced by alkyl;-   Y, independently for each occurrence, represents H or CH₂O(CO)R₇,-   R₇, independently for each occurrence, represents H or substituted    or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl,    heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy;-   Z represents H or R₃(CO);-   R₁ and R₂ each independently represent H, alkyl, alkoxy or hydroxy,    preferably H;-   R₃ represents substituted or unsubstituted alkyl, hydroxyalkyl,    aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl,    arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,    heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,    heteroaryloxy, heteroaryloxyalkyl or-   C(R₈)(R₉)(R₁₀), N(R₄)(R₅) or OR₆, wherein any free hydroxyl group    may be acylated to form C(O)R₇;-   R₄ and R₅ each independently represent H or substituted or    unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇;-   R₆, independently for each occurrence, represents substituted or    unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl,    alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl,    wherein any free hydroxyl group may be acylated to form C(O)R₇; and-   R₈, R₉ and R₁₀ each independently represent H or substituted or    unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino,    aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or    heteroaryloxyalkyl, or R₅ and R₉ together with the carbon to which    they are attached, form a carbocyclic or heterocyclic ring system,    wherein any free hydroxyl group may be acylated to form C(O)R₇, and    wherein at least two of R₈, R₉ and R₁₀ are not H;-   R₁₁ represents substituted or unsubstituted aryl, arylalkyl,    aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy,    or heteroaryloxyalkyl, or C(R₁₂)(R₁₃)(R₁₄), N(R₄)(R₁₄) or OR₁₄,    wherein any free hydroxyl group may be acylated to form C(O)R₇;-   R₁₂ and R₁₃ each independently represent H or substituted or    unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino,    aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino,    alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy,    aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or    heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated    to form C(O)R₇, and wherein both of R₁₂ and R₁₃ are not H; and-   R₁₄ represents substituted or unsubstituted aryl, arylalkyl,    aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy,    or heteroaryloxyalkyl; and-   a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or    docetaxel;

wherein the subject is refractory to at least one prior chemotherapytreatment, preferably to treatment with a taxane.

In certain embodiments wherein alkyl, hydroxyalkyl, amino, acylamino,aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl,arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,heteroaryloxy, or heteroaryloxyalkyl are substituted, they aresubstituted with one or more substituents selected from substituted orunsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl),alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy,aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g.,trifluoromethylalkoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino,hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy,aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl(e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl,heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl,amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl,or acyl, including perfluoroacyl (e.g., C(O)CF₃)), carbonylalkyl (suchas carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl,including perfluoroacylalkyl (e.g., -alkylC(O)CF₃)), carbamate,carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone,sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl,alkylthio, thiocarbonyl (such as thioester, thioacetate, orthioformate), phosphoryl, phosphate, phosphonate or phosphinate.

In certain embodiments, R₁₁ represents substituted or unsubstitutedarylalkyl, such as substituted or unsubstituted benzyl.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂,CH₂S, SCH₂, or CH₂NHCH₂, wherein any hydrogen atom of a CH₂ unit may bereplaced by alkyl or alkoxy, and any hydrogen atom of a CH₂ unit ofCH₂CH₂, CH₂CH₂CH₂ or CH₂ may be replaced by hydroxyl. In certainembodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂, preferablyCH₂CH₂. In certain embodiments, L is not CH₂SCH₂.

In certain embodiments, each Y represents H. In other embodiments, atleast one Y is CH₂O(CO)R₇.

In certain embodiments, X represents S or CH═CH. In certain embodiments,X represents S.

In certain embodiments, R₁ and R₂ each represent H.

In certain embodiments, Z represents R₃(CO). In certain embodimentswherein Z is R₃(CO), R₃ and R₁₁ are not identical (e.g., the compound offormula I is not symmetrical).

In certain embodiments, Z represents R₃(CO) and R₃ represents arylalkyl,heteroarylalkyl, cycloalkyl or heterocycloalkyl. In certain embodiments,Z represents R₃(CO) and R₃ represents C(R₈)(R₉)(R₁₀), wherein R₈represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl,arylalkyl or heteroaryl, R₉ represents H, and R₁₀ represents hydroxy,hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl oralkoxy. In certain embodiments, Z represents R₃(CO) and R₃ representsheteroarylalkyl.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂, suchas CH₂CH₂, Y represents H, X represents S, Z represents R₃(CO), R₁ andR₂ each represent H, R₃ represents arylalkyl, heteroarylalkyl,cycloalkyl or heterocycloalkyl, and R₁₁ represents arylalkyl. In certainsuch embodiments, R₃ represents heteroarylalkyl.

In certain embodiments, L represents CH₂SCH₂, CH₂CH₂, CH₂S or SCH₂, suchas CH₂CH₂, Y represents H, X represents S, Z represents R₃(CO), R₁ andR₂ each represent H, and R₃ represents C(R₈)(R₉)(R₁₀), wherein R₈represents aryl, arylalkyl, heteroaryl or heteroaralkyl, such as aryl,arylalkyl or heteroaryl, R₉ represents H, and R₁₀ represents hydroxy,hydroxyalkyl, alkoxy or alkoxyalkyl, such as hydroxy, hydroxyalkyl oralkoxy, and R₁₁ represents arylalkyl. In certain such embodiments, R₈represents heteroaryl.

In certain embodiments, L represents CH₂CH₂, Y represents H, Xrepresents S or CH═CH, such as S, Z represents R₃(CO), R₁ and R₂ eachrepresent H, R₃ represents substituted or unsubstituted arylalkyl,heteroarylalkyl, cycloalkyl or heterocycloalkyl, and R₁₁ representsarylalkyl. In certain such embodiments, R₃ represents heteroarylalkyl.

In certain embodiments, L represents CH₂CH₂, Y represents H, Xrepresents S, Z represents R₃(CO), R₁ and R₂ each represent H, R₃represents C(R₈)(R₉)(R₁₀), wherein R₈ represents aryl, arylalkyl orheteroaryl, R₉ represents H, and R₁₀ represents hydroxy, hydroxyalkyl oralkoxy, and R₁₁ represents arylalkyl. In certain such embodiments, R₈represents aryl and R₁₀ represents hydroxyalkyl. In certain otherembodiments, R₈ represents heteroaryl. In certain embodiments, theglutaminase inhibitor is selected from any one of the compoundsdisclosed in Table 3 of PCT Application Publication Number WO2013/078123, published May 30, 2013, the contents of which areincorporated herein by reference in their entirety.

Preferably, the compound is selected from compound 1, 2, 6, 7, 8, 11,13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 35, 36, 38, 39, 40, 41, 43, 44, 47, 48, 50, 51, 52, 54, 55, 58, 63,64, 65, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 92, 93, 94, 95, 97, 99, 100, 102, 105, 107, 111, 112, 114,115, 116, 117, 118, 120, 121, 122, 123, 126, 127, 133, 135, 136, 138,140, 141, 143, 146, 147, 148, 152, 153, 155, 156, 157, 158, 159, 160,161, 162, 163, 164, 165, 166, 168, 169, 170, 172, 173, 174, 175, 176,177, 178, 179, 180, 181, 182, 185, 186, 187, 188, 189, 190, 193, 194,195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 208, 210, 211,213, 214, 216, 217, 219, 220, 226, 227, 228, 229, 231, 232, 234, 235,236, 237, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250,251, 252, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266,267, 268, 269, 270, 271, 273, 274, 275, 276, 278, 279, 280, 281, 282,283, 285, 286, 287, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298,299, 300, 302, 304, 1038, 306, 307, 308, 309, 310, 311, 313, 314, 315,316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 327, 329, 332, 333,334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 527,347, 348, 349, 350, 351, 352, 353, 354, 355, 358, 359, 360, 361, 362,363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376,377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390,391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404,405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418,419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432,433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446,447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460,461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474,475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488,489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502,503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,517, 518, 519, 520, 521, 522, 523, 528, 529, 530, 531, 532, 533, 534,535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548,549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562,563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576,577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590,591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604,605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618,619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632,633, 634, 635, 636, 638, 639, 640, 641, 644, 645, 646, 647, 648, 649,650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677,678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 692,693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 707,708, 709, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726,727, 728, 729, or 730.

In certain embodiments, the compound of formula (I) is Compound 354,also known as CB-839:

In certain embodiments, the invention provides a method of treating orpreventing cancer, such as triple-negative breast cancer, in a subject,comprising administering a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   X is a bond, —S—, —S(O)—, —SO₂—, —CH═CH—, or —C(O)—;-   each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—,    provided that (1) at least one of W, Y and Z is not —CH═ and (2)    when one of W is —S— and the Y in the same ring is N, then the Z in    the same ring is not —CH═;-   each R¹ and R² is independently C₁₋₆ alkylene-R⁴, —N(R³)—R⁴,    —N(R³)—C(O)—R⁴, —C(O)—N(R³)—R⁴, —N(R³)—C(O)—O—R⁴,    —N(R³)—C(O)—N(R³)—R⁴, —O—C(O)—N(R³)—R⁴, —N(R³)—C(O)—C₁₋₆    alkylene-C(O)—R⁴, —N(R³)—C(O)—C₁₋₆ alkylene-N(R³)—C(O)—R⁴ or    —N(R^(3a))—C(O)—CH₂—N(R³)—C(O)—R⁴;-   each R³ is independently hydrogen, C₁₋₆ alkyl or aryl;-   each R⁴ is independently C₁₋₆ alkyl, C₁₋₆ alkenyl, aryl, heteroaryl,    aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cycloalkyl    or cycloalkylalkyl, each of which is substituted with 0-3    occurrences of R⁵, or two adjacent R⁵ moieties, taken together with    the atoms to which they are attached form a heterocyclyl,    heteroaryl, cycloalkyl or aryl;-   each R⁵ is independently oxo (═O), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    alkoxy, cyano, halo, —OH, —SH, —OCF₃, —SO₂—C₁₋₆ alkyl, —NO₂,    —N(R⁷)—C(O)—C₁₋₆ alkyl, —N(R⁶)₂, —O—C(O)—C₁₋₆ alkyl, C₃₋₇    cycloalkyl, (C₃₋₇cycloalkyl)alkyl, aryl, aryloxy, —C(O)-aryl,    heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl or    heterocyclyl, wherein each aryl, heteroaryl or heterocyclyl is    further substituted with 0-3 occurrences of R⁷;-   each R⁶ is independently hydrogen, fluoro, OH or C₁₋₆ alkyl;-   each R⁷ is independently hydrogen, C₁₋₆ alkyl, —OH, —SH, cyano,    halo, —CF₃, —OCF₃, —SO₂—C₁₋₆ alkyl, —NO₂, —N(R⁷)—C(O)—C₁₋₆ alkyl,    —N(R⁶)₂ or C₁₋₆ alkoxy;-   m is 1, 2 or 3;-   n is 1, 2 or 3; provided that when X is bond, the sum of m and n is    from 3 to 6 and when X is —S—, —S(O)—, —SO₂—, —CH═CH—, or —C(O)—,    the sum of m and n is from 2 to 4;-   o is 1, 2 or 3; and-   p is 1, 2 or 3;-   with the proviso that:-   (1) when X is —S—, m and n are both 2, each R⁶ is H, then (i) R¹ and    R² are not both —NHC(O)—R⁴, wherein R⁴ is C₁₋₆ alkyl, monocyclic    aryl, monocyclic heteroaryl, monocyclic aralkyl, monocyclic    heteroaralkyl and each member of R⁴ is substituted with 0-3    occurrences of R⁵; and (ii) R¹ and R² are not both —NHC(O)O-methyl,    —NHC(O)O-ethyl, —NHC(±)-6-pyrimidine-2,4(1H,3H)-dionyl, or    —NHC(O)NH-phenyl wherein said phenyl of the —NHC(O)NH-phenyl moiety    is optionally substituted with 1 or 2 groups selected from methyl,    nitro, and halo;-   (2) when X is —S—, m and n are both 1, each R⁶ is H, then (i) R¹ and    R² are not both —NH-phenyl or —NH-4-methoxy-phenyl;-   (3) when X is a bond, the sum of m and n is 3, each R⁶ is H, then R¹    and R² are not both NHC(O)-phenyl;-   (4) when X is a bond, m and n are both 2, each R⁶ is H, then R¹ and    R² are not both —NHC(O)-furanyl, —NHC(O)-phenyl,    —NHC(O)-o-methoxy-phenyl, —NHC(O)—C₁₋₆ alkyl, —NH-benzyl, or    —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is    substituted with 0-3 occurrences of R⁵;-   (5) when X is a bond, the sum of m and n is 5, each R⁶ is H, then R¹    and R² are not both —NHC(O)—C₁₋₆ alkyl, —NHC(O)-cyclohexyl, or    —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is    optionally substituted with methyl; and-   (6) when X is a bond, m and n are both 3, each R⁶ is H, then R¹ and    R² are not both NH-phenyl;-   preferably wherein the compound of formula (II) is administered with    a meal; and a taxane, such as paclitaxel, nab-paclitaxel,    cabazitaxel or docetaxel;-   wherein the subject is refractory to at least one prior chemotherapy    treatment, preferably to treatment with a taxane.

In certain embodiments, W is —S—, each Y is —N═, and each Z is —N═.

In certain embodiments, W is —CH═, each Z is —O—, and each Y is —N═.

In certain embodiments, o is 1 and p is 1.

In certain embodiments, R¹ and R² are each —N(R³)—C(O)—O—R⁴.

In certain embodiments, the compound having the structure of Formula(II) has the structure of Formula (IIa):

In certain embodiments, R¹ and R² are the same.

In certain embodiments, the compound having the structure of Formula(II) is a compound having the structure of Formula (IIb):

In certain embodiments, the invention provides a method of treating orpreventing cancer, such as triple-negative breast cancer, in a subject,comprising administering a compound of formula (III):

wherein:

-   X is C₃-C₇ cycloalkylene;-   each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—,    provided that at least one of W, Y and Z is not —CH═;-   each R¹ and R² is independently —NH₂, —N(R³)—C(O)—R⁴,    —C(O)—N(R³)—R⁴, —N(R³)—C(O)—O—R⁴, —N(R³)—C(O)—N(R³)—R⁴ or    —N(R³)—C(O)—SR⁴;-   each R³ is independently hydrogen, C₁₋₆ alkyl or aryl;-   each R⁴ is independently C₁₋₆ alkyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, or    heterocyclyl, each of which is substituted with 0-3 occurrences of    R⁵;-   each R⁵ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, —O—C₁₋₆    alkyleneC₁₋₆ alkoxy, C₁₋₆ thioalkoxy, C₁₋₆ haloalkyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, heterocyclylalkyl, heterocyclyl, cyano, halo, oxo,    —OH, —OCF₃, —OCHF₂, —SO₂—C₁₋₆ alkyl, —NO₂, —N(R⁷)—C(O)—C₁₋₆ alkyl,    —C(O)N(R⁷)₂, —N(R⁷)S(O)₁₋₂—C₁₋₆ alkyl, —S(O)₂N(R⁷)₂, —N(R⁷)₂, —C₁₋₆    alkylene-N(R⁷)₂, wherein said alkyl, C₁₋₆ alkoxy,    —O—C₁₋₆alkyleneC₁₋₆alkoxy, C₁₋₆ thioalkoxy, C₁₋₆ haloalkyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylalkyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, heterocyclylalkyl, heterocyclyl, —SO₂—C₁₋₆alkyl,    —NO₂, —N(R⁷)—C(O)—C₁₋₆ alkyl, —C(O)N(R⁷)₂, —N(R⁷)S(O)₁₋₂—C₁₋₆alkyl,    —S(O)₂N(R⁷)₂, —N(R⁷)₂, or —C₁₋₆alkylene-N(R⁷)₂ is optionally    substituted with 0-3 occurrences of R⁸; or two adjacent R⁵ moieties,    taken together with the atoms to which they are attached form a    cycloalkyl or heterocyclyl;-   each R⁶ is independently hydrogen, fluoro, C₁₋₆ alkyl, —OH, —NH₂,    —NH(CH₃), —N(CH₃)₂, or C₁₋₆ alkoxy;-   each R⁷ is independently hydrogen or C₁₋₆ alkyl;-   each R⁸ is independently halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, —OH,    —N(R⁷)₂, or C₁₋₆alkoxy, —O—C₁₋₆ alkyleneC₁₋₆ alkoxy, CN, NO₂,    —N(R⁷)—C(O)—C₁₋₆alkyl, —C(O)N(R⁷)₂, —N(R⁷)S(O)₁₋₂C₁₋₆ alkyl, or    —S(O)₂N(R⁷)₂;-   m is 0, 1, or 2;-   n is 0, 1, or 2;-   o is 1, 2 or 3; and-   p is 1, 2 or 3; provided that (1) when X is unsubstituted    cyclopropyl, R¹ and R² are not both NH-phenyl; and (2) X is other    than substituted cyclobutyl or substituted cyclopentyl;-   preferably wherein the compound of formula (III) is administered    with a meal; and-   a taxane, such as paclitaxel, nab-paclitaxel, cabazitaxel or    docetaxel;-   wherein the subject is refractory to at least one prior chemotherapy    treatment, preferably to treatment with a taxane.

In certain embodiments, W is —S—, each Y is —N═, and each Z is —N═.

In certain embodiments, o is 1 and p is 1.

In certain embodiments, m is O and n is O. Alternatively, m and n caneach be 1.

In certain embodiments, R¹ and R² are different. Alternatively, R¹ andR² can be the same.

In certain embodiments, R¹ and R² are each —N(R³)—C(O)—O—R⁴, whereineach R³ is hydrogen and each R⁴ is aralkyl or heteroaralkyl, each ofwhich is substituted with 0-3 occurrences of R⁵.

In certain embodiments, the compound having the structure of Formula(III) is a compound having the structure of Formula (IIIa):

In certain embodiments, the compound having the structure of Formula(III) is a compound having the structure of Formula (IIIb):

In certain embodiments, the compound having the structure of Formula(III) has the structure of formula (IIIc):

In certain embodiments, the compound of formula (III) is a compound offormula (IV):

wherein q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound of formula (III) has the structureof formula (IVa):

wherein q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound of formula (III) has the structureof formula (IVb):

wherein q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound of formula (III) has the structureof formula (IVc):

wherein q is 0, 1, 2, 3, or 4.

Compounds of any of Formulae (II) to (IV) are alternatively referred toherein as “glutaminase inhibitors.”

Taxanes are a class of chemotherapeutics that share a complexfunctionalized bicyclic ring system. Taxanes have been used in treatinga number of cancers, such as bladder cancer, breast cancer, esophagealcancer, gastric cancer, head & neck cancer, Kaposi's sarcoma, lungcancer (including non-small cell lung cancer and small cell lungcancer), melanoma, ovarian cancer, pancreatic cancer, penile cancer,prostate cancer, testicular germcell cancer, thymoma and thymiccarcinoma. Further cancers include cholangiocarcinoma, biliary cancer,gallbladder cancer, uterine cancer, cervical cancer, and occult primaryor cancer of unknown primary. Representative taxanes include paclitaxel,docetaxel, cabazitaxel, larotaxel, tesetaxel, BMS-184476, and NBT-287.In certain embodiments, the taxane is docetaxel. In certain embodiments,the taxane is cabazitaxel. In certain embodiments, the taxane isnab-paclitaxel. In certain preferred embodiments, the taxane ispaclitaxel. In most preferred embodiments, the method comprisesadministering the taxane to which the subject is refractory.

As used herein, the term “refractory” describes a subject whose disease(e.g., tumor) is unresponsive to a particular therapy. Refractorysubjects can have a lesser response than the treatment's efficacy intypical, responsive patients, a response that diminishes or terminatesafter an initial period of responsiveness to the treatment, or noresponse to the treatment (e.g., the tumor continues to grow). A“response” to a method of treatment can include a decrease in oramelioration of negative symptoms, a decrease in the progression of adisease or symptoms thereof, an increase in beneficial symptoms orclinical outcomes, a lessening of side effects, stabilization ofdisease, partial or complete remedy of disease, among others. In thetreatment of cancer, a response typically indicates a reduced rate ofgrowth for a tumor, a cessation of tumor growth, or a shrinkage of atumor. Similarly, a response may indicate a lack of new tumors(metastases). A refractory subject, on the other hand, may experiencetumor growth or the appearance of additional tumors (metastases) despitereceiving the therapeutic treatment. Subjects that are refractory to atreatment may have responded initially but then became resistant to thetreatment over time. Other subjects never significantly respond to thetreatment.

In certain embodiments, a subject may be refractory to any knownchemotherapeutic treatment as disclosed above and herein, includingpaclitaxel, nab-paclitaxel, cabazitaxel or docetaxel monotherapy.Subjects as described herein have already been dosed with one or morechemotherapeutic agents that are not a compound of formula (I) and theyare refractory to one or more of those agent(s). The prior chemotherapytreatment can be selected from one or more of the additionalchemotherapeutic agents that are, in some embodiments, administeredconjointly with the compound of formula (I) and the taxane. Theseadditional chemotherapeutic agents and their administration are furtherdiscussed herein and below. In certain embodiments, the priorchemotherapy treatment can be administration of one or morechemotherapeutic agents selected from a PARP inhibitor, carboplatin,tamoxifen, paclitaxel, cyclophosphanamide and doxorubicin. In certainembodiments, the prior chemotherapy treatment comprised administrationof paclitaxel as a single chemotherapeutic agent or in combination withone or more other chemotherapeutic agents.

The methods described herein are useful for the treatment of a widevariety of cancers, including bladder cancer, breast cancer, esophagealcancer, gastric cancer, head & neck cancer, Kaposi's sarcoma, lungcancer (including non-small cell lung cancer and small cell lungcancer), melanoma, ovarian cancer, pancreatic cancer, penile cancer,prostate cancer, testicular germcell cancer, thymoma and thymiccarcinoma. In certain embodiments, the subject has breast cancer, suchas triple-negative breast cancer, that is locally advanced. In otherembodiments, the subject has metastatic breast cancer, such asmetastatic triple-negative breast cancer.

In certain embodiments, compounds of the invention may be prodrugs ofthe compounds of formula I or Ia, e.g., wherein a hydroxyl in the parentcompound is presented as an ester or a carbonate, or carboxylic acidpresent in the parent compound is presented as an ester. In certain suchembodiments, the prodrug is metabolized to the active parent compound invivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, orcarboxylic acid).

In certain embodiments, compounds of the invention may be racemic. Incertain embodiments, compounds of the invention may be enriched in oneenantiomer. For example, a compound of the invention may have greaterthan about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70%ee, about 80% ee, about 90% ee, or even about 95% or greater ee. Incertain embodiments, compounds of the invention may have more than onestereocenter. In certain such embodiments, compounds of the inventionmay be enriched in one or more diastereomer. For example, a compound ofthe invention may have greater than about 30% de, about 40% de, about50% de, about 60% de, about 70% de, about 80% de, about 90% de, or evenabout 95% or greater de.

In certain embodiments, the present invention relates to methods oftreating or preventing cancer, such as triple-negative breast cancer,with a compound of formula (I) or (Ia), or a pharmaceutically acceptablesalt thereof, and a taxane, such as paclitaxel, nab-paclitaxel,cabazitaxel or docetaxel. In certain embodiments, the therapeuticpreparation may be enriched to provide predominantly one enantiomer of acompound (e.g., of formula I or Ia). An enantiomerically enrichedmixture may comprise, for example, at least about 60 mol percent of oneenantiomer, or more preferably at least about 75, about 90, about 95, oreven about 99 mol percent. In certain embodiments, the compound enrichedin one enantiomer is substantially free of the other enantiomer, whereinsubstantially free means that the substance in question makes up lessthan about 10%, or less than about 5%, or less than about 4%, or lessthan about 3%, or less than about 2%, or less than about 1% as comparedto the amount of the other enantiomer, e.g., in the composition orcompound mixture. For example, if a composition or compound mixturecontains about 98 grams of a first enantiomer and about 2 grams of asecond enantiomer, it would be said to contain about 98 mol percent ofthe first enantiomer and only about 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of formula Ior Ia). A diastereomerically enriched mixture may comprise, for example,at least about 60 mol percent of one diastereomer, or more preferably atleast about 75, about 90, about 95, or even about 99 mol percent.

In certain embodiments, the present invention provides a pharmaceuticalpreparation suitable for use in a human patient, comprising any of thecompounds shown above (e.g., a compound of the invention, such as acompound of formula I or Ia), and one or more pharmaceuticallyacceptable excipients. In certain embodiments, the pharmaceuticalpreparations may be for use in treating or preventing a condition ordisease as described herein. In certain embodiments, the pharmaceuticalpreparations have a low enough pyrogen activity to be suitable for usein a human patient.

Any of the disclosed compounds may be used in the manufacture ofmedicaments for the treatment of any diseases or conditions disclosedherein.

Uses of Enzyme Inhibitors

In certain embodiments, the method of treating or preventing cancer,such as triple-negative breast cancer, may comprise administering acompound of the invention conjointly with one or more otherchemotherapeutic agent(s).

Chemotherapeutic agents that may be conjointly administered withcompounds of the invention include: ABT-263, afatinib dimaleate,axitinib, aminoglutethimide, amsacrine, anastrozole, asparaginase,AZD5363, Bacillus Calmette-Guérin vaccine (bcg), bicalutamide,bleomycin, bortezomib, buserelin, busulfan, cabozantinib, campothecin,capecitabine, carboplatin, carfilzomib, carmustine, ceritinib,chlorambucil, chloroquine, cisplatin, cladribine, clodronate,cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin,dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol,docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, filgrastim,fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide,gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea,idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone,lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine,lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin,mitotane, mitoxantrone, MK-2206, mutamycin, nilutamide, nocodazole,octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib,pemexetred, pentostatin, perifosine, PF-04691502, plicamycin,pomalidomide, porfimer, procarbazine, raltitrexed, ramucirumab,rituximab, romidepsin, rucaparib, selumetinib, sirolimus, sorafenib,streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide,temsirolimus, teniposide, testosterone, thalidomide, thioguanine,thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab,tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine,and vorinostat (SAHA). In other embodiments, chemotherapeutic agentsthat may be conjointly administered with compounds of the inventioninclude: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502,romidepsin, and vorinostat (SAHA). In certain embodiments of the methodsof the invention described herein, the chemotherapeutic agent conjointlyadministered with compounds of the invention is a taxanechemotherapeutic agent, such as paclitaxel, nab-paclitaxel, cabazitaxelor docetaxel. In certain embodiments of the methods of the inventiondescribed herein, the chemotherapeutic agent conjointly administeredwith compounds of the invention is doxorubicin. In certain embodimentsof the methods of the invention described herein, a compound of theinvention is administered conjointly with a taxane chemotherapeuticagent (e.g., paclitaxel) and doxorubicin.

Many combination therapies have been developed for the treatment ofcancer. In certain embodiments, compounds of the invention may beconjointly administered with a combination therapy. Examples ofcombination therapies with which compounds of the invention may beconjointly administered are included in Table 1.

TABLE 1 Exemplary combinatorial therapies for the treatment of cancer.Name Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVDDoxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast)Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC(Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide,Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin,Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, DaunorubicinB-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine,Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPPBleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine,Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, CisplatinBIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine,Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin,Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin,Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine,Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin,Methotrexate, Procarbazine CAP Cyclophosphamide, Doxorubicin, CisplatinCAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV andEtoposide CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide CCCyclophosphamide, Carboplatin CDDP/VP-16 Cisplatin, Etoposide CEFCyclophosphamide, Epirubicin, Fluorouracil CEPP(B) Cyclophosphamide,Etoposide, Prednisone, with or without/Bleomycin CEV Cyclophosphamide,Etoposide, Vincristine CF Cisplatin, Fluorouracil or CarboplatinFluorouracil CHAP Cyclophosphamide or Cyclophosphamide, Altretamine,Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine,Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, PrednisoneCHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin,Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMFMethotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide,Methotrexate, Fluorouracil, Prednisone CMFVP Cyclophosphamide,Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin,Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone,Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine,Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin,Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine,Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine,Methotrexate, Prednisone Cooper Regimen Cyclophosphamide, Methotrexate,Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine,Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPPCyclophosphamide, Vincristine, Procarbazine, Prednisone CP(ChronicChlorambucil, Prednisone lymphocytic leukemia) CP (Ovarian Cancer)Cyclophosphamide, Cisplatin CVD Cisplatin, Vinblastine, Dacarbazine CVICarboplatin, Etoposide, Ifosfamide, Mesna CVP Cyclophosphamide,Vincristine, Prednisome CVPP Lomustine, Procarbazine, Prednisone CYVADICCyclophosphamide, Vincristine, Doxorubicin, Dacarbazine DA Daunorubicin,Cytarabine DAT Daunorubicin, Cytarabine, Thioguanine DAV Daunorubicin,Cytarabine, Etoposide DCT Daunorubicin, Cytarabine, Thioguanine DHAPCisplatin, Cytarabine, Dexamethasone DI Doxorubicin, IfosfamideDTIC/Tamoxifen Dacarbazine, Tamoxifen DVP Daunorubicin, Vincristine,Prednisone EAP Etoposide, Doxorubicin, Cisplatin EC Etoposide,Carboplatin EFP Etoposie, Fluorouracil, Cisplatin ELF Etoposide,Leucovorin, Fluorouracil EMA 86 Mitoxantrone, Etoposide, Cytarabine EPEtoposide, Cisplatin EVA Etoposide, Vinblastine FAC Fluorouracil,Doxorubicin, Cyclophosphamide FAM Fluorouracil, Doxorubicin, MitomycinFAMTX Methotrexate, Leucovorin, Doxorubicin FAP Fluorouracil,Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FEC Fluorouracil,Cyclophosphamide, Epirubicin FED Fluorouracil, Etoposide, Cisplatin FLFlutamide, Leuprolide FZ Flutamide, Goserelin acetate implant HDMTXMethotrexate, Leucovorin Hexa-CAF Altretamine, Cyclophosphamide,Methotrexate, Fluorouracil IDMTX/6-MP Methotrexate, Mercaptopurine,Leucovorin IE Ifosfamide, Etoposie, Mesna IfoVP Ifosfamide, Etoposide,Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2 Vincristine,Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-IIIMethotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MACCMethotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-BMethotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine,Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazinem-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine,Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin,Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil,Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna,Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide,Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, MitomycinMOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine,Vincristine, Procarbazine, Prednisone MOPP/ABV Mechlorethamine,Vincristine, Procarbazine, Prednisone, Doxorubicin, Bleomycin,Vinblastine MP (multiple myeloma) Melphalan, Prednisone MP (prostatecancer) Mitoxantrone, Prednisone MTX/6-MO Methotrexate, MercaptopurineMTX/6-MP/VP Methotrexate, Mercaptopurine, Vincristine, PrednisoneMTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breastcancer) Mitomycin, Vinblastine MV (acute myelocytic Mitoxantrone,Etoposide leukemia) M-VAC Methotrexate Vinblastine, Doxorubicin,Cisplatin MVP Mitomycin Vinblastine, Cisplatin MVPP Mechlorethamine,Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil,Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine,Prednisone, Doxorubicin OPPA Add Procarbazine to OPA. PAC Cisplatin,Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CICisplatin, Doxorubicin PCV Lomustine, Procarbazine, Vincristine PFLCisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine,Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin,Cyclophosphamide, Etoposide ProMACE/cytaBOM Prednisone, Doxorubicin,Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine,Methotrexate, Leucovorin, Cotrimoxazole PRoMACE/MOPP Prednisone,Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine,Procarbazine, Methotrexate, Leucovorin Pt/VM Cisplatin, Teniposide PVAPrednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine,Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMFStreptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin,Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone TTTMethotrexate, Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide,Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine,Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, CyclophosphamideVACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin,Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATHVinblastine, Doxorubicin, Thiotepa, Flouxymesterone VBAP Vincristine,Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine,Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAPVincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine,Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIPEtoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCPVincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide,Cisplatin V-TAD Etoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with/,Daunorubicin or Idarubicin or Mitoxantrone “8 in 1” Methylprednisolone,Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin,Cytarabine, Dacarbazine

Examples of combination therapies with which compounds of the inventionmay be conjointly administered include cisplatin and fluorouracil; andifosfamide, mesna, and cisplatin.

In certain embodiments, the conjoint therapies of the invention furthercomprise conjoint administration with other types of chemotherapeuticagents, such as immuno-oncology agents. Cancer cells often have specificcell surface antigens that can be recognized by the immune system. Thus,immuno-oncology agents, such as monoclonal antibodies, can selectivelybind to cancer cell antigens and effect cell death. Otherimmuno-oncology agents can suppress tumor-mediated inhibition of thenative immune response or otherwise activate the immune response andthus facilitate recognition of the tumor by the immune system. Exemplaryimmuno-oncology agents, include, but are not limited to, abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat,epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab,isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab,ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab,rituximab, ticilimumab, samalizumab, and tremelimumab. Thus, in someembodiments, the methods of the invention further comprise conjointadministration of one or more immuno-oncology agents, such as the agentsmentioned above.

In certain embodiments, a compound of the invention may be conjointlyadministered with non-chemical methods of cancer treatment. In certainembodiments, a compound of the invention may be conjointly administeredwith radiation therapy. In certain embodiments, a compound of theinvention may be conjointly administered with surgery, withthermoablation, with focused ultrasound therapy, with cryotherapy, orwith any combination of these.

In certain embodiments, different compounds of the invention may beconjointly administered with one or more other compounds of theinvention. Moreover, such combinations may be conjointly administeredwith other therapeutic agents, such as other agents suitable for thetreatment of cancer, immunological or neurological diseases, such as theagents identified above. In certain embodiments, conjointlyadministering one or more additional chemotherapeutic agents with acompound of the invention provides a synergistic effect. In certainembodiments, conjointly administering one or more additionalchemotherapeutics agents provides an additive effect.

In certain embodiments, the present invention provides a kit comprising:a) one or more single dosage forms of a glutaminase inhibitor; b) one ormore single dosage forms of a taxane such as paclitaxel, nab-paclitaxel,cabazitaxel or docetaxel, as mentioned above; and c) instructions forthe administration of the glutaminase inhibitor and the taxane for thetreatment of cancer, such as triple-negative breast cancer.

The present invention provides a kit comprising:

-   -   a) a pharmaceutical formulation (e.g., one or more single dosage        forms) comprising a glutaminase inhibitor and a taxane; and    -   b) instructions for the administration of the pharmaceutical        formulation, e.g., for treating or preventing cancer, such as        triple-negative breast cancer.

In certain embodiments, the kit further comprises instructions for theadministration of the pharmaceutical formulation comprising aglutaminase inhibitor conjointly with a taxane as mentioned above. Incertain embodiments, the kit further comprises a second pharmaceuticalformulation (e.g., as one or more single dosage forms) comprising achemotherapeutic agent as mentioned above.

DEFINITIONS

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-trifluoroethyl, etc. C₀alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represents a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure. The term “aminoalkyl”, as used herein, refers to an alkylgroup substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably, the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond.

The term “carbocycle” includes 5-7 membered monocyclic and 8-12 memberedbicyclic rings. Each ring of a bicyclic carbocycle may be selected fromsaturated, unsaturated and aromatic rings. Carbocycle includes bicyclicmolecules in which one, two or three or more atoms are shared betweenthe two rings. The term “fused carbocycle” refers to a bicycliccarbocycle in which each of the rings shares two adjacent atoms with theother ring. Each ring of a fused carbocycle may be selected fromsaturated, unsaturated and aromatic rings. In an exemplary embodiment,an aromatic ring, e.g., phenyl, may be fused to a saturated orunsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Anycombination of saturated, unsaturated and aromatic bicyclic rings, asvalence permits, is included in the definition of carbocyclic. Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane,1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fusedcarbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene andbicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one ormore positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to an “aryl”group or moiety implicitly includes both substituted and unsubstitutedvariants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁹ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

The term “protecting group” refers to a group of atoms that, whenattached to a reactive functional group in a molecule, mask, reduce orprevent the reactivity of the functional group. Typically, a protectinggroup may be selectively removed as desired during the course of asynthesis. Examples of protecting groups can be found in Greene andWuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley& Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

The term “healthcare providers” refers to individuals or organizationsthat provide healthcare services to a person, community, etc. Examplesof “healthcare providers” include doctors, nurses, nurse practitioners,hospitals, continuing care retirement communities, skilled nursingfacilities, subacute care facilities, clinics, multispecialty clinics,freestanding ambulatory centers, home health agencies, HMO's and PPO's.

The term “subject” to which administration is contemplated includes, butis not limited to, humans (i.e., a male or female of any age group,e.g., a pediatric subject (e.g., infant, child, adolescent) or adultsubject (e.g., young adult, middle-aged adult or senior adult)) and/orother primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals,including commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs; and/or birds, including commerciallyrelevant birds such as chickens, ducks, geese, quail, and/or turkeys.Preferred subjects are humans.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample.

The term “treating” includes prophylactic and/or therapeutic treatments.The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the subject of one or more of the disclosedcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thesubject) then the treatment is prophylactic (i.e., it protects thesubject against developing the unwanted condition), whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present invention (e.g., a compound of formula I). Acommon method for making a prodrug is to include one or more selectedmoieties which are hydrolyzed under physiologic conditions to reveal thedesired molecule. In other embodiments, the prodrug is converted by anenzymatic activity of the subject. For example, esters or carbonates(e.g., esters or carbonates of alcohols or carboxylic acids) arepreferred prodrugs of the present invention. In certain embodiments,some or all of the compounds of formula I in a formulation representedabove can be replaced with the corresponding suitable prodrug, e.g.,wherein a hydroxyl in the parent compound is presented as an ester or acarbonate or carboxylic acid present in the parent compound is presentedas an ester.

Pharmaceutical Compositions

The compositions and methods of the present invention may be utilized totreat a subject in need thereof. In certain embodiments, the subject isa mammal such as a human, or a non-human mammal. When administered tosubject, such as a human, the composition or the compound is preferablyadministered as a pharmaceutical composition comprising, for example, acompound of the invention and a pharmaceutically acceptable carrier.Pharmaceutically acceptable carriers are well known in the art andinclude, for example, aqueous solutions such as water or physiologicallybuffered saline or other solvents or vehicles such as glycols, glycerol,oils such as olive oil, or injectable organic esters. In a preferredembodiment, when such pharmaceutical compositions are for humanadministration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, for example, to effect delayed release of an agent or toselectively target one or more cells, tissues or organs. Thepharmaceutical composition can be in dosage unit form such as tablet,capsule (including sprinkle capsule and gelatin capsule), granule,lyophile for reconstitution, powder, solution, syrup, suppository,injection or the like. The composition can also be present in atransdermal delivery system, e.g., a skin patch. The composition canalso be present in a solution suitable for topical administration, suchas an eye drop.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a selfemulsifying drug delivery systemor a selfmicroemulsifying drug delivery system. The pharmaceuticalcomposition (preparation) also can be a liposome or other polymermatrix, which can have incorporated therein, for example, a compound ofthe invention. Liposomes, for example, which comprise phospholipids orother lipids, are nontoxic, physiologically acceptable and metabolizablecarriers that are relatively simple to make and administer.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The compound may also be formulated for inhalation. In certainembodiments, a compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thesubject being treated, the particular mode of administration. The amountof active ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatable with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinaceous biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the subject being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the subject's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the invention. A larger total dose canbe delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

In certain embodiments, the dosing follows a 3+3 design. The traditional3+3 design requires no modeling of the dose-toxicity curve beyond theclassical assumption for cytotoxic drugs that toxicity increases withdose. This rule-based design proceeds with cohorts of three patients;the first cohort is treated at a starting dose that is considered to besafe based on extrapolation from animal toxicological data, and thesubsequent cohorts are treated at increasing dose levels that have beenfixed in advance. In some embodiments, the three doses of a compound offormula (I) range from about 100 mg to about 1000 mg orally, such asabout 200 mg to about 800 mg, such as about 400 mg to about 700 mg, suchas about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg,and further such as about 500 mg to about 600 mg. Dosing can be threetimes a day when taken with without food, or twice a day when taken withfood. In certain embodiments, the three doses of a compound of formula(I) range from about 400 mg to about 800 mg, such as about 400 mg toabout 700 mg, such as about 500 mg to about 800 mg, and further such asabout 500 mg to about 600 mg twice a day. In certain preferredembodiments, a dose of greater than about 600 mg is dosed twice a day.

If none of the three patients in a cohort experiences a dose-limitingtoxicity, another three patients will be treated at the next higher doselevel. However, if one of the first three patients experiences adose-limiting toxicity, three more patients will be treated at the samedose level. The dose escalation continues until at least two patientsamong a cohort of three to six patients experience dose-limitingtoxicities (i.e., ≥about 33% of patients with a dose-limiting toxicityat that dose level). The recommended dose for phase II trials isconventionally defined as the dose level just below this toxic doselevel.

In certain embodiments, the dosing schedule can be about 40 mg/m² toabout 100 mg/m², such as about 50 mg/m² to about 80 mg/m², and furthersuch as about 70 mg/m² to about 90 mg/m² by IV for 3 weeks of a 4 weekcycle.

In certain embodiments, compounds of the invention may be used alone orconjointly administered with another type of therapeutic agent. As usedherein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe second compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the subject, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either concomitantly or sequentially. Incertain embodiments, the different therapeutic compounds can beadministered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72hours, or a week of one another. Thus, a subject who receives suchtreatment can benefit from a combined effect of different therapeuticcompounds.

In certain embodiments, conjoint administration of compounds of theinvention with one or more additional therapeutic agent(s) (e.g., one ormore additional chemotherapeutic agent(s)) provides improved efficacyrelative to each individual administration of the compound of theinvention (e.g., compound of formula I or Ia) or the one or moreadditional therapeutic agent(s). In certain such embodiments, theconjoint administration provides an additive effect, wherein an additiveeffect refers to the sum of each of the effects of individualadministration of the compound of the invention and the one or moreadditional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts ofcompounds of the invention in the compositions and methods of thepresent invention. In certain embodiments, contemplated salts of theinvention include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, Na, Ca, K, Mg, Zn orother metal salts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

In certain embodiments, the invention relates to a method for conductinga pharmaceutical business, by manufacturing a formulation of a compoundof the invention, or a kit as described herein, and marketing tohealthcare providers the benefits of using the formulation or kit fortreating or preventing any of the diseases or conditions as describedherein.

In certain embodiments, the invention relates to a method for conductinga pharmaceutical business, by providing a distribution network forselling a formulation of a compound of the invention, or kit asdescribed herein, and providing instruction material to patients orphysicians for using the formulation for treating or preventing any ofthe diseases or conditions as described herein.

In certain embodiments, the invention comprises a method for conductinga pharmaceutical business, by determining an appropriate formulation anddosage of a compound of the invention for treating or preventing any ofthe diseases or conditions as described herein, conducting therapeuticprofiling of identified formulations for efficacy and toxicity inanimals, and providing a distribution network for selling an identifiedpreparation as having an acceptable therapeutic profile. In certainembodiments, the method further includes providing a sales group formarketing the preparation to healthcare providers.

In certain embodiments, the invention relates to a method for conductinga pharmaceutical business by determining an appropriate formulation anddosage of a compound of the invention for treating or preventing any ofthe disease or conditions as described herein, and licensing, to a thirdparty, the rights for further development and sale of the formulation.

EXAMPLES Example 1: Synthesis of CB-839:2-phenyl-N-(6-(4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)acetamide

The synthesis of CB-839 is as described for compound 354 inWO/2014/089048, incorporated herein by reference in its entirety.

Example 2: GLC Activity in TNBC Cell Lines

Glutaminase activity was measured in homogenates prepared from tumorcell lines using the coupled assay as described in Gross et al. (2014)Mol Cancer Ther 13:890.

In measuring glutaminase activity in homogenates, the backgroundactivity that is independent of glutaminase was measured from reactionsthat lacked glutamine. Background activity was subtracted from activityin the presence of glutamine. The specific activity of glutaminase wascalculated by dividing the background-subtracted glutaminase activity bythe total protein amount present in the reaction. The extent of cellgrowth or cell loss (i.e., a decrease in cell number relative to thetime of compound addition) was determined following treatment with 1 μMCB-839 for 72 h.

In FIG. 1, the correlation between cell proliferation or loss measuredafter CB-839 treatment is plotted on the x-axis and glutaminase specificactivity plotted on the y-axis.

Example 3: CB-839 Enhances the Anti-Tumor Activity of Paclitaxel in anIn Vivo TNBC Model

In the JIMT-1 xenograft model, the antitumor efficacy was evaluated bytreating established tumors (125 mm³ at the start of dosing) with CB-839both as a single agent and in combination with paclitaxel, astandard-of-care chemotherapeutic agent for the treatment of TNBC. Theregimen for paclitaxel (five doses at 10 mg/kg delivered every other dayat the start of study) was chosen to provide suboptimal efficacy toensure a window to evaluate the potential impact of combinationtreatment. As shown in FIG. 2, oral dosing of CB-839 alone (200 mg/kgBID) resulted in 54% tumor growth inhibition (TGI) relative to vehiclecontrol at study end (P=0.004). Single agent paclitaxel caused aninitial regression of the JIMT-1 tumors that was followed by a rapidregrowth resulting in a TGI of 73% relative to vehicle control at theend of study (P=0.0002). Combination of CB-839 with paclitaxel largelysuppressed the regrowth of the tumors resulting in a TGI relative tovehicle control of 100% at the end of study (P<0.0001 vs. vehicle andP=0.0025 vs. paclitaxel alone).

Example 4: Clinical Study of TNBC Patient Treatment withCB-839+Paclitaxel

A Phase 1 study of CB-839 in advanced solid tumors (CX-839-001) wasinitiated using a “3+3” dose escalation as monotherapy and incombination with standard of care agents. For the TNBC cohort, the keyeligibility criteria was locally advanced/metastatic TNBC, refractorydisease with prior paclitaxel therapy allowed. Presented in FIG. 3 isthe length of time patients receiving CB-839 in combination with weeklypaclitaxel (80 mg/m2 IV for three weeks of a four week cycle stayed onthe study. Response status was determined using the RECIST criteria(Eisenhauer et al. (2009) EJC 45:228).

Example 5: RECIST Response for TNBC Patients in a Clinical Study ofTreatment with CB-839+Paclitaxel

The RECIST response for each TNBC patient receiving CB-839 incombination with paclitaxel was determined according to percent changein target tumors as described in Eisenhauer et al (2009). The percentchange was then correlated to the dose of CB-839 received (FIG. 4) orthe length of time the patient stayed on the study (FIG. 5).

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control. The compounds, synthetic methods, andexperimental protocols and results of U.S. application Ser. No.13/680,582, filed Nov. 19, 2012, are hereby incorporated by reference.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

The invention claimed is:
 1. A method of treating cancer in a subject,comprising administering a glutaminase inhibitor and a taxane to thesubject, wherein the subject is refractory to a taxane; the glutaminaseinhibitor is

and the cancer is triple negative breast cancer.
 2. The method of claim1, wherein administering the taxane comprises administering paclitaxel,nab-paclitaxel, cabazitaxel or docetaxel.
 3. The method of claim 1,wherein administering the taxane comprises administering paclitaxel. 4.The method of claim 1, wherein administering the taxane comprisesadministering docetaxel.
 5. The method of claim 1, further comprisingconjointly administering one or more additional chemotherapeutic agents.6. The method of claim 5, wherein the one or more additionalchemotherapeutic agents are selected from bortezomib, capecitabine,carboplatin, carfilzomib, cyclophosphamide, daunorubicin, doxorubicin,epirubicin, eribulin, fluorouracil, gemcitabine, ixabepilone,lenalidomide, methotrexate, mitoxantrone, mutamycin, rituximab,thiotepa, vincristine, and vinorelbine.
 7. The method of claim 6,wherein the one or more additional chemotherapeutic agents are selectedfrom bortezomib, carfilzomib, doxorubicin, lenalidomide, and rituximab.8. The method of claim 5, wherein the additional chemotherapeutic agentis an immuno-oncology agent.
 9. The method of claim 1, wherein thetaxane to which the subject is refractory is paclitaxel or docetaxel.10. The method of claim 9, wherein the taxane to which the subject isrefractory is paclitaxel.
 11. The method of claim 9, wherein the taxaneto which the subject is refractory is docetaxel.
 12. The method of claim2, wherein the taxane to which the subject is refractory is paclitaxelor docetaxel.
 13. The method of claim 12, wherein the taxane to whichthe subject is refractory is paclitaxel.
 14. The method of claim 12,wherein the taxane to which the subject is refractory is docetaxel. 15.The method of claim 3, wherein the taxane to which the subject isrefractory is paclitaxel or docetaxel.
 16. The method of claim 15,wherein the taxane to which the subject is refractory is paclitaxel. 17.The method of claim 15, wherein the taxane to which the subject isrefractory is docetaxel.